The diagnosis of urothelial cancer (renal pelvis cancer, ureteral cancer, and bladder cancer) depends greatly on radiographic diagnostic imaging and histopathological diagnosis of a lesion collected with a ureteroscope or a cystoscope. However, the former, radiographic diagnostic imaging, has difficulty in detection of a non-invasive tumor and has difficulty in differentiating between a calculus or an inflammatory lesion and a cancer, although it is a non-invasive diagnostic method. On the other hand, the latter, histopathological diagnosis, is an invasive diagnostic method in which insertion of an endoscope through the urethra causes devastating agonies to the patient, although the method is high in diagnostic accuracy. Further, since it is necessary to find diseased tissue with the endoscope and collect the diseased tissue, manipulation of the endoscope and determination of the diseased tissue require much skill. Furthermore, even if the endoscope has successfully been inserted into the body, an accurate diagnosis cannot be made unless diseased tissue is finally found.
Under such circumstances, urine cytodiagnosis, which is low in invasiveness, has come to hold an extremely prominent position as a clinical examination method for urothelial cancer (referred to also as “urinary system tumor”). Urine cytodiagnosis is a method of diagnosis through observation of cancer cells appearing in the urine. Various types of cytology, such as urine cytodiagnosis, are disclosed, for example, in Non-patent Literatures 1 to 3.
Urine cytodiagnosis is a so-called non-invasive diagnosis that involves the use as a sample of the urine, which comes naturally out of the body of the patient. As such, urine cytodiagnosis is not painful to the patient. Further, ready availability of a sample makes it possible to perform an examination any number of times. However, urine cytodiagnosis has limitations in a case where the number of cells in a sample is small and in morphological determination of poorly atypical cancer cells, and requires much skill for determination of cancer cells. For this reason, in a case where the number of cells in a sample is small or in a case where the cells are not in a form sufficient to be judged as malignant, there is a risk that a diagnosis of cancer may not be made when it should be made. Further, there are a case where inflammation or the like may cause normal cells to exhibit atypia and a case where responsive tubular epithelial cells in particular may exhibit such atypia as to be taken as cancer. For this reason, there is a risk that non-cancer cells may be diagnosed as cancer cells. Therefore, the existing urine cytodiagnosis is said to be fatally low in diagnostic accuracy (sensitivity), although it is high in specificity (i.e. it has a low probability of diagnosing non-cancer cells as cancer cells). Furthermore, a urine specimen that is used as a sample in urine cytodiagnosis is easily denatured, and depending on handling of the urine specimen, an accurate diagnosis may not be made.
Therefore, there is a demand for the development of a urothelial cancer diagnostic system that is not invasive, i.e. not painful to the patient, and is high in diagnostic accuracy. It should be noted that while cancer markers are considered to be useful in the diagnosis of cancer, no cancer marker has been found yet that is effective in the diagnosis of urothelial cancer.
Through their previous molecular pathological studies of urothelial cancer, the inventors of the present invention found (i) that unlike normal cells, urothelial cancer cells produce an excess of reactive oxygen species (ROS) and (ii) that labelling of ROS allows discrimination of cancer cells from normal cells (see Non-patent Literature 4).
Incidentally, it was revealed that amyotrophic lateral sclerosis (ALS), which causes a gradual decline of muscle strength and finally leads to general anesthesia, is caused by abnormalities in ubiquilin 2 (see Non-patent Literature 5). Ubiquilin 2 has a role in promoting the restoration and utilization of defective or damaged proteins within nerve cells. It is said that when ubiquilin 2 does not function normally, damaged proteins accumulate in nerve cells to severely destroy the nerve cells.
Ubiquilin 2 is a member belonging to the ubiquilin family, and known members other than ubiquilin 2 include ubiquilin 1, ubiquilin 3, and ubiquilin 4. Patent Literatures 1 and 2 teach that ubiquilin 1 can be used as a tumor antigen against prostate cancer, lung cancer, or breast cancer. Further, Patent Literature 3 describes a method for the treatment of tumors, cancers, neoplasms, malignant tumors, and diseases due to proliferation or overproliferation of harmful or abnormal cells, and shows, as an example of its target cell, a cell expressing ubiquilin 1. Further, Patent Literature 4 discloses measuring an expression level of ubiquilin 4 as an index in a method for the detection of a cause of the pathogenesis of colorectal cancer. Further, Patent Literature 5 discloses an anticancer drug containing, as an active ingredient, a small molecule having ubiquilin-binding activity and topoisomerase II inhibitory activity.